Fever In A Neonate

Article Author:
Usha Avva
Article Editor:
Scarlet Benson
Updated:
3/5/2019 9:14:28 AM
PubMed Link:
Fever In A Neonate

Introduction

World Health organization categorize the neonatal sepsis into early and late based on the age of onset. Early neonatal sepsis affects infants less than 72 hours of age; whereas, we see late-onset infections in infants older than 72 hours to 28 days of age. Early recognition and treatment are necessary to decrease the significant morbidity and mortality in this age group.[1]

Etiology

The etiology of early onset neonatal sepsis is predominantly GBS infection followed by Escherichia coli sepsis. Risk factors are maternal Group B streptococcal colonization, chorioamnionitis, premature or prolonged (greater than 18 hours) rupture of membranes, preterm birth (less than 37 weeks) and multiple gestations.

The etiology of late-onset neonatal sepsis is from pathogens like Guillain-Barre syndrome (GBS), E. coli, Coagulase-negative Staphylococci, Staphylococcus aureus, Klebsiella pneumonia, Enterococci (more common in preterm infants), Pseudomonas, and Candida albicans. Risk factors for late-onset neonatal sepsis are prematurity, low birth weight, prolonged indwelling catheter use, invasive procedures, ventilator-associated pneumonia, and prolonged antibiotic usage.[1]

Epidemiology

WHO statistics say over one million neonatal deaths around the world each year result from the neonatal sepsis/pneumonia making it the leading cause of infant mortality, whereas pre-term infants are more at risk for the neonatal sepsis in the United States. According to the Centers for Disease Control and Prevention (CDC), it estimates the incidence of early onset neonatal sepsis in the United States to be 0.77 to 1 per 1000 live births. With the establishment of guidelines in universal screening and treating maternal GBS colonization, the incidence of early onset sepsis in full-term infants has decreased to 0.3 to 0.4/1000 live births.[2]

Pathophysiology

The activation of the pattern recognition receptors (PRR) like extracellular, toll-like receptors (TLRs) and intracellular NOD-like receptors (NLR) and RIG-like receptors (RLR) helps in recognition of a pathogen by the local immunity.  Gram-positive, gram-negative sepsis activates TLR2 and TLR4, respectively; whereas, the double-stranded virus activates TLR3. They start an immune response by producing proinflammatory cytokines which cause endothelial activation and damage causing SIRS, sepsis, and death. Premature neonates show dysregulation complement system making them susceptible to severe sepsis.[1]

Toxicokinetics

Host defense proteins like opsonin (CRP), haptoglobin, lactoferrin, serum amyloid A and pro calcitonin provide additional protection.  Septic neonates have decreased the production of Interleukins (IL-1beta, TNF-alpha, IEN-gamma, and IL-12). The quantitative and qualitative deficits in neutrophils, neutrophil depletion of bone marrow and their decreased deformability and delayed apoptosis play a significant role in neonatal sepsis-causing endothelial damage, DIC, and multi-organ failure.[3]

History and Physical

Neonatal sepsis has a varied presentation. The neonate could have hypo or hyperthermia, irritability or lethargy, apnea or tachypnea, bradycardia or tachycardia, poor feeding, excessive sleepiness or being fussy. Necrotizing enter colitis (NEC) is common in premature and very premature infants. The physical examination could be noncontributory or could show an ill-looking infant with abnormal or unstable vital signs.

A careful history is very important. History should include both maternal and infant risk factors. Maternal risk factors are prenatal care, maternal colonization, the intrapartum antibiotic use, maternal medical history including diabetes, hypertension, thyroid disease and maternal drug abuse. Infant risk factors are prematurity, birth weight, neonatal course, a detailed history of NICU stay, length of ruptured membranes, ill contact and detailed feeding history.[4]

Evaluation

You should get a white cell count, chemistry panel, and cultures of the blood, urine, cerebrospinal fluid (CSF), and body fluid.  We use a microscopic analysis of urine, CRP, and pro-calcitonin in the risk stratification process to identify infants at low risk for serious bacterial infection.  Based on the symptoms one could get Respiratory Pathogen panel or tests for RSV, influenza, gastrointestinal (GI) pathogen panel, a chest x-ray. Rochester criteria, Philadelphia criteria, and Boston criteria all call for full septic work up in infants less than 28 days of age regardless of their risk factors.[5] After the wide use of the streptococcal vaccination, the prevalence of bacteremia in febrile infants has decreased. Gomez et al. validated “Step by Step” approach [6] which showed that the risk stratification is a workable strategy to identify low-risk infant with fever. Infants with fever at high risk for serious bacterial infection have elevated leukocyturia, elevated pro-calcitonin (greater than 0.5 Ng/ml), CRP (greater than 20 mg/L) and ANC (greater than 10,000/mm3). Wallace and Brown et al.  showed that the frequency of bacterial meningitis with urinary tract infection (UTI) is minimal.[7] Greenhow et al. concluded that 24% of the well-looking neonates with fever born at Kaiser Permanente Northern California had none laboratory studies done and none of them had delayed bacteremia or meningitis.[8] Recently some centers are using the CSF molecular testing which has a turn around time of two hours to aid in the management of febrile neonates, especially during the enteroviral season. This test is also useful if the CSF is bloody are very abnormal to differentiate between bacterial and viral pathogens.

Treatment / Management

The ill-looking child requires full septic work and broad-spectrum antibiotic coverage with ampicillin and cefotaxime, the combination of which covers 100% of early neonatal infections and 93% of late-onset bacteremia. Gentamicin and penicillin can cover 94% of early infections.[9] Cefotaxime does not treat some Escherichia coli, Pseudomonas, Enterococci, Acinetobacter, and Listeria monocytogenes. Use of Cefotaxime in the NICU can cause outbreaks of drug-resistant nosocomial infections, which is a serious concern in many centers. Pediatric Infectious diseases specialist consider empiric treatment of neonatal herpes with Intravenous Acyclovir if the CSF has an elevated red cell count or in any ill-looking neonate with suspected herpes.[10] We admit and empirically treat ill-looking infants and infants with risk factors while waiting for the cultures.

Fluid resuscitation is different to treat septic shock. In term neonate, the fluid bolus is 20 ml/kg as rapidly as possible up to 60 ml/kg, whereas in the preterm neonate the fluid bolus comprises 10 ml/kg in 30 minutes and repeat if needed and then vasopressor support for the fluid refractory shock with dopamine and dobutamine. For catecholamine-resistant shock consider milrinone for old shock with poor LV function and normal blood pressure, nitrous oxide for low blood pressure and poor RV function,  vasopressin, or terlipressin and Inotropes for warm shock and low blood pressure and consider ECMO if the child develops persistent fetal circulation.

Based on the laboratory data, you can risk stratify the well-looking febrile infants greater than 21 days of age with no risk factors and with no source of invasive infection into high risk, medium risk and low risk.  You can safely observe low-risk infants at home or in the hospital without empiric treatment, meanwhile high-risk infants are observed and treated in the hospital. You also can observe medium-risk infants in the hospital or at home before treating them empirically.[11] If in doubt admit them to the pediatric unit for observation while waiting for the culture results.[12]

Differential Diagnosis

One can consider the following differential diagnoses. They are

  • Hypoglycemia
  • Congenital heart disease
  • Inborn errors of metabolism.
  • Congenital adrenal insufficiency
  • Congenital hypothyroidism
  • Neglect/abuse

Prognosis

Prognosis is excellent if treated early in full-term neonates. The prognosis is different in premature and very premature infants.

Enhancing Healthcare Team Outcomes

The outcome of well looking febrile infants is excellent with a care coordination between the emergency medicine providers and hospitalist service. Early recognition is the most important factor in decreasing the morbidity and mortality in neonatal sepsis. The septic premature infants require a dedicated team and cooperation among various specialists like the neonatologist, pediatric infectious disease specialists, intensivist and with specialized centers to provide ECMO for the optimum outcome. Take the help of the pharmacists and infectious disease specialists in choosing and in calculating the doses for the of empiric antibiotics in premature and full-term infants both in early onset and late onset neonatal sepsis.

The management of well looking previously healthy febrile infants from age 7-90 days is changing from the traditional teaching.  Infants from 7 to 28 days of age received full septic work up in 58% of the cases. That number dropped to 25% in infants aged 29 days-60 days, further dropped to 5% in infants aged 61 days to 90 days.[8] Evidence Level 2.

The modified Philadelphia criteria has high sensitivity and low specificity when applied to the febrile infants in this age of the improved vaccination as opposed to the age before Hemophilus influenza and streptococcal vaccination than the Rochester criteria. Evidence Level 2[13]


References

[1] Shah BA,Padbury JF, Neonatal sepsis: an old problem with new insights. Virulence. 2014 Jan 1     [PubMed PMID: 24185532]
[2] Qazi SA,Stoll BJ, Neonatal sepsis: a major global public health challenge. The Pediatric infectious disease journal. 2009 Jan     [PubMed PMID: 19106756]
[3] Simonsen KA,Anderson-Berry AL,Delair SF,Davies HD, Early-onset neonatal sepsis. Clinical microbiology reviews. 2014 Jan     [PubMed PMID: 24396135]
[4] Laptook AR,Bell EF,Shankaran S,Boghossian NS,Wyckoff MH,Kandefer S,Walsh M,Saha S,Higgins R, Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants. The Journal of pediatrics. 2018 Jan     [PubMed PMID: 29246358]
[5] Aronson PL,McCulloh RJ,Tieder JS,Nigrovic LE,Leazer RC,Alpern ER,Feldman EA,Balamuth F,Browning WL,Neuman MI, Application of the Rochester Criteria to Identify Febrile Infants With Bacteremia and Meningitis. Pediatric emergency care. 2019 Jan     [PubMed PMID: 29406479]
[6] Gomez B,Mintegi S,Bressan S,Da Dalt L,Gervaix A,Lacroix L, Validation of the "Step-by-Step" Approach in the Management of Young Febrile Infants. Pediatrics. 2016 Aug     [PubMed PMID: 27382134]
[7] Wallace SS,Brown DN,Cruz AT, Prevalence of Concomitant Acute Bacterial Meningitis in Neonates with Febrile Urinary Tract Infection: A Retrospective Cross-Sectional Study. The Journal of pediatrics. 2017 May     [PubMed PMID: 28185626]
[8] Greenhow TL,Hung YY,Pantell RH, Management and Outcomes of Previously Healthy, Full-Term, Febrile Infants Ages 7 to 90 Days. Pediatrics. 2016 Dec     [PubMed PMID: 27940667]
[9] Puopolo KM,Eichenwald EC, No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years. Pediatrics. 2010 May     [PubMed PMID: 20385650]
[10] Muller-Pebody B,Johnson AP,Heath PT,Gilbert RE,Henderson KL,Sharland M, Empirical treatment of neonatal sepsis: are the current guidelines adequate? Archives of disease in childhood. Fetal and neonatal edition. 2011 Jan     [PubMed PMID: 20584804]
[11] Hyde TB,Hilger TM,Reingold A,Farley MM,O'Brien KL,Schuchat A, Trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in San Francisco and Atlanta. Pediatrics. 2002 Oct     [PubMed PMID: 12359781]
[12] Madhi F,Jung C,Timsit S,Levy C,Biscardi S,Lorrot M,Grimprel E,Hees L,Craiu I,Galerne A,Dubos F,Cixous E,Hentgen V,Béchet S,Bonacorsi S,Cohen R, Febrile urinary-tract infection due to extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: A French prospective multicenter study. PloS one. 2018     [PubMed PMID: 29370234]
[13] Aronson PL,Wang ME,Shapiro ED,Shah SS,DePorre AG,McCulloh RJ,Pruitt CM,Desai S,Nigrovic LE,Marble RD,Leazer RC,Rooholamini SN,Sartori LF,Balamuth F,Woll C,Neuman MI, Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture. Pediatrics. 2018 Dec     [PubMed PMID: 30425130]